Age-related skeletal muscle atrophy, also known as sarcopenia, diminishes the health and quality of life of many Veteran patients. However, the molecular mechanisms of age-related muscle atrophy are poorly understood, and a pharmacologic therapy does not exist. As a result, many elderly Veterans suffer the consequences of muscle atrophy, including weakness, falls, debilitation, and loss of independence. This places enormous burdens on elderly Veterans, their families, and society in general. Our long-term goal is to understand molecular mechanisms of age-related muscle atrophy, and then use that information to develop a therapy. In the previous grant cycle, we discovered Gadd45a and p21 as critical mediators of a novel molecular pathway to skeletal muscle atrophy. Aging, as well as other causes of muscle atrophy, strongly induce Gadd45a mRNA in skeletal muscle of humans, mice and rats. This increases the level of Gadd45a protein, which in turn increases p21 mRNA. As a result, the level of p21 protein rises and triggers many of the critical changes that occur during age-related skeletal muscle atrophy, including loss of protein and mitochondria, and ultimately, muscle fiber atrophy. Collectively, these results strongly suggest a key role for the Gadd45a/p21 pathway in age-related muscle atrophy. However, these data also elucidate several important areas for further investigation. For example, our data indicate that the sequential induction of Gadd45a and p21 plays a central role in skeletal muscle atrophy; but we do not yet know how aging increases skeletal muscle Gadd45a expression, or how Gadd45a increases p21 expression. In addition, our data suggest the Gadd45a/p21 pathway as a potential therapeutic target in age-related skeletal muscle atrophy; but this hypothesis has not yet been tested. To resolve these important issues, we propose three specific aims, all using mouse models. In Aim 1, we will test the hypothesis that two transcription factors (p53 and ATF4) are responsible for increasing Gadd45a mRNAs during skeletal muscle aging. In Aim 2, we will test the hypothesis that two Gadd45a-interacting proteins (MEKK4 and LRRC14) play key roles in Gadd45a-mediated p21 expression. In Aim 3, we will test the hypothesis that reducing Gadd45a and/or p21 permits recovery of skeletal muscle mitochondria and muscle fiber size in aged, atrophic muscle. Through these studies, we hope to elucidate fundamental molecular mechanisms and new therapeutic approaches for age-related muscle atrophy, a disabling condition that affects many Veteran patients.